Angiotensin converting enzyme inhibitors and vasodilators
Introduction
Heart failure (HF) is a complex syndrome, characterized by neurohumoral activation. That increased activation of the renin–angiotensin–aldosterone system (RAAS) plays a central role in the pathophysiology of chronic HF, has been recognized for many years.1 However, until the latter part of the 20th century, the pharmacological management of chronic HF was limited to correction of fluid and electrolyte disturbances (diuretics) and augmentation of myocardial contractility (cardiac glycosides).
The situation is very different now; physicians caring for patients with HF have at their disposal an armamentarium of powerful pharmacological therapies, encompassing angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, aldosterone receptor antagonists, and β-receptor blockers, in addition to our old friends diuretics and digoxin. To a greater or lesser extent, the newer agents act to inhibit activity of the RAAS, emphasizing the crucial role of this system in the HF syndrome. Among the agents with proven efficacy in the management of HF, ACE inhibitors have the most extensive evidence base, and, in head-to head comparisons with alternative RAAS inhibitors, remain unsurpassed in terms of clinical benefit.2–4
This chapter considers briefly the development and pharmacology of ACE inhibitors, their physiological actions, and the evidence base for their prescription to patients with HF. It also discusses the side effect profile of ACE inhibitors.
Development of ACE inhibitors
It is little remembered that ACE inhibitors for oral administration were designed for the purpose of inhibiting angiotensin converting enzyme, based on the ACE-inhibiting action of peptides from South American pit viper venom, and on similarities between ACE and the pancreatic digestive enzyme carboxypeptidase A. The known zinc dependence of ACE led Ondetti and Cushman5 to incorporate a sulphydryl moiety in their original dipeptide ACE inhibitor, captopril. Subsequent ACE inhibitor molecules were developed to bind to sites on the ACE molecule other than the zinc atom, with varying aims of increasing duration of action or potency, or to increase absorption. Of currently available ACE inhibitors, only captopril binds via a sulphydryl ligand, fosinopril via a phosphinyl group, and the remainder via a carboxyl ligand.6 These differences are associated with pharmacokinetic and pharmacodynamic differences, the clinical significance of which is unclear in the management of patients with HF.
Physiology
The RAAS is a ubiquitous endocrine system, and ACE is found in the circulation as well as in many tissues. The enzyme has a number of potential substrates, the most relevant to the use of ACE inhibitors in HF being angiotensin I and bradykinin.
A number of claims has been made for one or other ACE inhibitor having properties of high affinity for, and inhibition of, tissue ACE. In reality, ACE inhibitors block tissue ACE and plasma ACE with the same rank-order of potency. Again, the clinical relevance of differences among ACE inhibitors in this context is unclear. In HF, ACE inhibition leads to reduced plasma angiotensin II and aldosterone levels, with subsequently lower systemic blood pressure via reduction in peripheral vascular resistance. In contrast to other vasodilator drugs, the fall in systemic vascular resistance is not accompanied by reflex tachycardia, possibly due to interaction between angiotensin II and the sympathetic nervous system. Plasma potassium concentrations increase. Left-sided cardiac pressures fall rapidly after ACE inhibition, as does pulmonary artery pressure, and cardiac index increases. Importantly, these changes, beneficial in the setting of HF, are maintained with chronic dosing and in exercise. Cardiac work and myocardial oxygen demand is reduced, and left ventricular ejection fraction (LVEF) tends to increase, at least with chronic treatment.
The magnitude of the blood pressure response to ACE inhibition is often a concern to physicians caring for patients with HF. Indeed, in the early years of ACE inhibitor use, it was common practice for patients to be admitted to hospital for initiation of therapy. This seldom, if ever, happens now. Prediction of the magnitude of blood pressure response in an individual patient is very difficult, and we will return to this clinical issue later in the chapter.
In clinical practice, ACE inhibitor therapy is well tolerated in the vast majority of patients. Measured changes in systemic blood pressure are seldom associated with clinically meaningful symptoms, although they do occur in a minority of patients. While accumulation of bradykinin appears to contribute to the fall in blood pressure after ACE inhibition in normal individuals,7 it is not known whether the accumulation occurs in people with HF. Moreover, the relevance to the survival benefits of ACE inhibition is doubtful, given the consistent equivalence or superiority of ACE inhibitors over angiotensin receptor blockers (ARBs) in clinical studies to date. Importantly, the acute haemodynamic response to ACE inhibition is poor predictor of clinical benefit.8
ACE inhibitors in clinical practice
Captopril, the first orally administered ACE inhibitor, was demonstrated in 1979 to lower left ventricular filling pressure and systemic vascular resistance in HF.9 Sustained beneficial haemodynamic effects were demonstrated soon afterwards.10
The earliest evidence of survival benefit from vasodilators in HF came from two studies in the mid 1980s,11,12 with the first evidence for benefit of ACE inhibitors coming from a trend to survival in the captopril multicenter research trial.13 Since then, ACE inhibitors have become perhaps the most extensively investigated class of drug in any branch of medicine, and certainly in HF, with tens of thousands of patients enrolled in clinical trials, and many millions treated in clinical practice.
Clinical trials of ACE inhibitors in chronic heart failure
The first randomized, controlled trial to show a clear benefit from ACE inhibition in CHF was the CONSENSUS study.14 In what would now be considered a very small trial, 127 patients were randomized to receive enalapril at a dose of 2.5–40 mg once daily, and 126 received matching placebo. The patient group chosen for this trial was at high risk, being a population of patients with advanced HF and New York Heart Association (NYHA) class IV symptoms. Over an average follow-up of 6 months, crude mortality of 44% in the placebo group was reduced to 26% in those treated with enalapril, a relative risk reduction of 40%, which was ascribed entirely to reduction in death from progressive HF.
Perhaps the magnitude of benefit in this trial was fortuitous, but case-fatality in the placebo group was indeed representative of that seen in such patients at the time. An important point is that a consistent finding in trials of ACE inhibition in HF is that those patients with the most severe disease have the greatest relative benefit from intervention.
CONSENSUS was one of two landmark trials which demonstrated the benefit of enalapril in patients with chronic, symptomatic HF. The other was the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial,15 which recruited patients with less symptomatic HF, mostly NYHA II–III. In SOLVD, 2569 patients were randomized to receive enalapril 2.5–10 mg twice daily (n = 1285) daily or placebo (n = 1284). The summary statistics for the results of these two trials are shown in Table 37.1.
Table 37.1 Summary statistics from CONSENSUS and SOLVD (Treatment) trials
Deaths | NNT | Additional findings | ||||
|---|---|---|---|---|---|---|
Number | RRR | ARR | ||||
CONSENSUS NYHA IV LVEF ≤40% | Enalapril n = 127 | 33 (26%) | 40%a (p = 0.002) | 18% | 7 (over average of 6 months) | Reduced NYHA class; reduced heart size |
Placebo n = 126 | 55 (44%) | |||||
SOLVD-T NYHA II–III LVEF ≤35% | Enalapril n = 1285 | 452 (35.2%) | 16% (p = 0.0036) | 4.5% | 22 (over average of 41 months) | 26% reduction HF hospitalization |
Placebo n = 1284 | 510 (39.7%) | |||||
SOLVD-PNYHA ILVEF ≤35% | Enalapril n = 2111 | 313 (14.8%) | 8% (p = 0.30) | 1% | N/A | 20% RRR in risk of death or HF hospitalization |
Placebo n = 2117 | 334 (15.8%) | |||||
a 6-month mortality RRR. 1-year RRR was 31%ARR, absolute risk reduction; HF, heart failure; LVEF, left ventricular ejection fraction; NNT, number needed to treat to delay one death; NYHA, New York Heart Association; RRR, relative risk reduction.
The absolute and relative risk reductions seen in these trials, and the numbers of patients needed to treat to achieve one event saved, are clear and consistent, and it is on the basis of these result that we base our use of ACE inhibitors in chronic HF. The observations are also supported by a meta-analysis of smaller randomized trials, which also reported improved survival, reduced hospitalization, and improvement in quality of life and exercise capacity.16
ACE inhibitors in asymptomatic heart failure
Between them, CONSENSUS (NYHA IV) and SOLVD treatment (NYHA II–III) addressed the efficacy of patients with symptomatic HF and reduced LVEF. As ACE inhibition produces benefit primarily by interfering with pathophysiological processes, rather than with symptoms, the SOLVD prevention trial examined the effect of enalapril, in the same doses as used in the treatment trial, in patients with asymptomatic left ventricular systolic dysfunction (LVSD).17 As shown in Table 37.1, the effects on mortality were of lesser magnitude than in the other trials, but there was a statistically significant benefit in the composite of death or HF hospitalization. Thus, there is evidence or the use of ACE inhibitors in chronic LVSD irrespective of symptom severity.
Why might the benefit in asymptomatic patients be so much less than in those with symptoms, in the context of similar LVEF? There are of course a myriad of potential explanations, but the observation perhaps demonstrates the limitations of assessing the severity of HF using LVEF as a dichotomized variable. In the current era, we have much more sensitive tools by which we may make this assessment, in particular plasma biomarkers such as natriuretic peptides. However, great reliance continues to be put upon (usually echocardiographic) assessment of LVEF. The potential usefulness of contemporary measures should be borne in mind when assessing an individual patient with HF.
Clinical trials of ACE inhibitors after acute myocardial infarction
For patients with chronic HF, starting treatment with an ACE inhibitor is secondary prevention therapy introduced at very variable time points in the natural history of an individual’s disease progression. As the single largest contributing cause of chronic HF is coronary artery disease, starting ACE inhibitors in patients with acute myocardial infarction (AMI) in the coronary care unit represents an opportunity to start treatment early in the course of the disease. Following the results of CONSENSUS and SOLVD, it was logical that the impact of ACE inhibition should be investigated in patients early following AMI.
The randomized, placebo-controlled clinical trials of ACE inhibition following AMI have varied in terms of eligibility criteria, timing of initiation of therapy in relation to the index event, and duration of follow-up. Overall, the trials can be divided helpfully into (1) those which initiated ACE inhibition in the acute phase of AMI, recruited patients irrespective of evidence of HF or LVSD, and continued therapy for a relatively short period of time and (2) those which initiated therapy more remote from the index MI, recruited patients with evidence of impaired left ventricular function, and continued therapy over a longer period.
Early ACE inhibition
Four major trials have investigated the effects of ACE inhibition initiated 0–36 h after the onset of symptoms of myocardial infarction (MI), together including nearly 100 000 patients.18–21 These trials—CONSENSUS II,18 GISSI-3,19 ISIS-4,20 and CCS-121—enrolled patients within 24 h18–20 or 36 h21 of onset of symptoms, and investigated captopril,20,21 lisinopril,19 or enalapril18 administered over 28 days20,21, 42 days,19 or 6 months.18
Reassuringly, in a meta-analysis, there was no evidence of heterogeneity among the results of the four trials.22 Over the first 30 days of follow-up, mortality was 7.1% in patients allocated to ACE inhibitor, and 7.6% in patients allocated to comparator treatment, a 7% relative risk reduction (p = 0.004), and corresponding to approximately 5 fewer deaths per 1000 patients treated for 30 days. Remarkably, 80% of these deaths were avoided in the first 7 days of treatment, corresponding to 4 fewer deaths per 1000 treated patients. The incidence of nonfatal HF was also reduced over the first 30 days.22
The CONSENSUS II study18 is unique among outcome studies of ACE inhibition in HF in that treatment was initiated with intravenous enalaprilat, followed by oral enalapril. It is also the only randomized, controlled trial of ACE inhibition in which the point estimate of the magnitude of effect was indicative of harm. The implications of this are discussed below.
Across the four trials, the absolute and proportional benefits of ACE inhibition were similar in men and women, and across age groups. It is important to note that absolute benefits were greater in patients at higher risk of adverse outcome; thus, patients with high heart rate, high Killip class at entry, with anterior MI or with prior MI or diabetes had greater absolute benefit.
Later ACE inhibition
Several randomized controlled trials have studied the efficacy of initiation of ACE inhibition after AMI but commenced beyond the very early phase. The trials have also been characterized by restriction of eligibility to patients with clinical or echocardiographic evidence of left ventricular dysfunction, and have observed the effects of therapy over at least a year.
The three largest such trials were SAVE,23 AIRE,24 and TRACE,25 which respectively studied captopril, ramipril, and trandolapril, each started at least 3 days after the acute event. As with the trials of early ACE inhibition, meta-analysis indicates the absence of heterogeneity among the results, with significant overall benefit.26 Across the three trials, median duration of treatment was 31 months, during which case-fatality in patients receiving ACE inhibitor was 23.4% compared to 29.1% for placebo, an absolute reduction of 5.7% and an odds ratio for mortality of 0.74 (95% CI 0.66–0.83). This equates to 60 fewer deaths per 1000 patients treated for 30 months. Survival benefit was evident within a few weeks of initiation of treatment (Fig. 37.1).
From Flather MD,Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients Lancet 2000;355:1575–81.
In the longer-term trials in patients with impaired left ventricular function, ACE inhibition was also associated with reduced risk of hospitalization with HF, and of reinfarction.
Adverse events in post myocardial infarction ACE inhibitor trials
The potential benefits of ACE inhibition after MI are clear; treatment is associated with statistically, and clinically, significant benefits. The benefits were not achieved without unwanted effects. In the short-term early-treatment trials18–21 persistent hypotension occurred in 17.6% and 9.3% of ACE inhibitor and control patients respectively, an excess of 84 per 1000 patients treated. Although there were more cases of cardiogenic shock and renal dysfunction in ACE inhibitor-treated patients compared with placebo (4.6 and 6.2 per 1000 respectively), absolute event rates were very small.
In the trials in which an ACE inhibitor was started rather later and continued for longer,23–25 hypotension (14.7% in ACE inhibitor-treated patients compared with 8.7% in placebo-treated patients; OR 1.86, p 〈 0.0001) and renal dysfunction (5.2% ACE inhibitor compared with 3.6% placebo; OR 1.49, p 〈 0.0001) were more common with active therapy, but again the absolute rates were low.
ACE inhibition after acute myocardial infarction—which patients?
The studies of early (〈36 h) initiation show a relatively small overall benefit using an all-inclusive, unselective approach to treatment; the benefit is seen within the first 7 days, and is of greater absolute magnitude in patients with higher baseline risk. The benefits are countered (to some degree) by a greater likelihood of important adverse events within the same time frame, including cardiogenic shock.22 The adverse events were particularly evident in the CONSENSUS II trial, which addressed the hypothesis that very early ACE inhibition with intravenous enalaprilat would be of clinical benefit. That CONSENSUS II refuted the hypothesis serves as a caution against the introduction of powerful pharmacological therapy in the very early period after AMI.
The studies of later introduction of ACE inhibition, recruiting patients with evidence of left ventricular impairment followed for longer periods, showed greater absolute benefit as the studies included only higher risk patients. Benefit was again evident from an early time after initiation of treatment.
Overall, the data support the prescription of ACE inhibitor from around day 3 after MI, in patients with evidence of left ventricular dysfunction. In patients without evidence of significant LVSD, additional criteria suggesting that there is likely to be benefit from treatment should be considered; prior or concomitant conditions (e.g. diabetes or prior MI, hypertension), the site (anterior) or extent of MI (high cardiac enzymes or troponin) should encourage the use of ACE inhibitor.
In Europe, current guidelines27 recommend prescription of ACE inhibitor for patients with LVEF below 40%.27 Other (UK national) guideline documents recommend that ACE inhibition should be considered for all patients with HF due to LVSD.28 In reality, in many countries ACE inhibition is prescribed to the majority of patients after MI, or with a diagnosis of HF, irrespective of left ventricular function. This is pragmatic, and safe for the vast majority of patients, but caution should be exercised; after AMI, very early treatment should be avoided, and care should be taken in patients with impaired renal function and in haemodynamically compromised individuals. In the future, more sophisticated methods may be used to identify patients likely to benefit from therapy, such as the circulating concentration of one or more biomarker.
The patients at highest risk have the most to gain from treatment. However, such patients are often the most challenging to treat with ACE inhibition, and indeed with other pharmacological therapies; they may present with extensive infarction or severe HF, low blood pressure, and renal impairment. It is in the management of these individuals that physicians best demonstrate their clinical expertise. In practice a clinically pragmatic approach may be adopted; if the patient has sufficient blood pressure to maintain cerebral (i.e. no, or minimal, symptoms of hypotension), and renal (maintenance of appropriate renal function) perfusion, then that patient has adequate blood pressure. This avoids the often knee-jerk response to low brachial blood pressure which leads to withdrawal of disease-modifying therapy.
An alternative to ACE inhibitor in chronic heart failure? Comparative studies
A number of studies have compared the clinical efficacy of ACE inhibitors to alternative pharmacological therapy. Indeed, one of the earliest trials to investigate the clinical effects of ACE inhibitors in HF was a comparison of enalapril against the combination of hydralazine and isosorbide dinitrate, the second Veterans Administration Heart Failure Trial, VHeFT II.29
More recent studies have investigated the comparative benefits of ACE inhibitors and angiotensin receptor antagonists, the class of agent which has become the alternative RAAS inhibitor. The first such trial, ELITE, Evaluation of Losartan in The Elderly, suggested that losartan in a target dose of 50 mg once daily was associated with over 40% improved survival compared to captopril.30 Unsurprisingly, this result stimulated enormous interest in the angiotensin receptor antagonists, and led to a number of large, properly powered studies. ELITE was a safety and tolerability study in only approximately 700 patients, and the subsequent definitive outcome trial, ELITE II, showed no superiority of losartan over captopril.31
ACE inhibitors have also stood up to the test of comparison with ARBs. Losartan has once again been compared with captopril, in the OPTIMAAL (Optimal Trial In Myocardial Infarction with the angiotensin II antagonist Losartan) trial.32 The results of this trial, summarized in Table 37.2, confirmed the (statistically nonsignificant) superiority of the ACE inhibitor captopril, at a mean dose of 45 mg three times daily, compared to losartan at a mean dose of 44 mg once daily. A later post MI trial, VALIANT, studied the comparative survival benefits of captopril, valsartan, or the combination of the two agents. VALIANT demonstrated very similar survival benefit for captopril compared to valsartan, with no evidence of added benefit, and greater side effects, from the combination of the two.33
Table 37.2 Summary of clinical endpoints for treatment with losartan or with captopril in the OPTIMAAL trial32
Losartan | Captopril | RR losartan vs captopril | p value | |
|---|---|---|---|---|
All-cause mortality | 499 (18.2%) | 447 (16.4%) | 1.13 (0.99–1.28) | 0.069 |
Myocardial reinfarction | 384 (14.0%) | 379 (13.9%) | 1.03 (0.89–1.18) | 0.722 |
Cardiovascular mortality | 420 (15.3%) | 363 (13.3%) | 1.17 (1.01–1.34) | 0.032 |
First all-cause hospitalization | 1806 (65.8%) | 1774 (64.9%) | 1.03 (0.97–1.10) | 0.362 |
First HF hospitalization | 306 (11.2%) | For 265 (9.7%) | 1.16 (0.98–1.37) | 0.072 |
HF, heart failure; RR, relative risk.
Overall, the evidence is compelling for the use of ACE inhibitors in patients with LVSD in patients with HF or following AMI. No alternative single agent has been shown to be superior to ACE inhibitors in improving both mortality and morbidity.
Side effect profile
The ACE inhibitors are generally very well tolerated and have a side effect profile predictable from their pharmacology; they lower blood pressure and glomerular perfusion in the kidney, and inhibition of neutral endopeptidase leads to accumulation of bradykinin. The resulting potential effects are: symptomatic hypotension, renal impairment, and cough. It is important to remember that each of these side effects is commonly found in patients with HF irrespective of ACE inhibitor therapy.
Renal impairment is a common accompaniment to HF, and there is a small absolute risk of significant worsening following initiation of ACE inhibitor therapy. In the SAVE, TRACE, and SOLVD studies, renal impairment was recorded in 5.2% of patients treated with ACE inhibitor compared to 3.6% of patients receiving placebo.26 In clinical practice patients at risk of developing renal dysfunction are not easy to identify, but renovascular disease is more prevalent among patients with peripheral vascular disease. Thus, the finding of reduced or absent peripheral (foot) pulses indicates a patient at risk of renovascular disease. It is important to remember that a degree of deterioration in renal function is to be expected after introduction or up-titration of ACE inhibitor therapy. A small increase in urea and creatinine should not lead to withdrawal of ACE therapy. Changes in renal function should always be considered in the context of the patient’s quality of life and prognosis, and in the context of the potential consequences of denial of disease-modifying ACE inhibitor treatment.
Cough is common in patients with HF, and is often incorrectly assumed to be secondary to the patient’s ACE inhibitor. The clinical response to withdrawal of treatment should always be monitored.
A lowering of blood pressure is an expected consequence of ACE inhibitor therapy, and this alone should not raise concerns of health care professionals caring for those with HF. In contrast, hypotension leading to symptoms is of more concern and may limit therapy. While often described as ‘first-dose hypotension’, and considered by many to occur only at the initiation of treatment, the blood pressure response to an individual dose of a given ACE inhibitor is the same after many months of treatment as it is to the very first dose.33,34
The variation in the blood pressure response to the very first dose of ACE inhibitor can be gauged from Fig. 37.2, which shows the individual mean arterial pressure responses to the first dose of oral enalapril 2.5 mg in 24 patients with HF.35 While the maximum average fall in mean arterial pressure was 15 mmHg, it ranged from zero to over 40 mmHg; importantly the time to the maximum fall varied enormously, from 2 to 8 h.
Although a number of physiological variables have been reported to be associated with the magnitude of the blood pressure response to ACE inhibition, it is in reality very difficult to predict in an individual patient with HF. Murray et al.35 attempted to identify clinical variables predicting the magnitude of the blood pressure fall in response to initiation of ACE inhibition in 144 patients with HF. Age, sex, NYHA class, diuretic dose, sodium, potassium, creatinine concentration, serum ACE activity, and plasma renin concentration were not predictive of the fall in blood pressure. At best, the combination of plasma renin activity, creatinine, age, the ACE inhibitor, and baseline blood pressure explained less than 25% of the blood pressure response. It is of note that in these patients with HF, higher baseline blood pressure was associated with a greater fall in response to ACE inhibition.
Finally, a small fall in haemoglobin may be observed during ACE inhibitor treatment, possibly as a consequence of the role of angiotensin II in the formation of erythroid precursors. The magnitude of fall in haematocrit is seldom more than 5%; the overall risk of a clinically significant change is very small and is associated with higher creatinine and with concurrent weight loss,36 both of which are more common in advanced HF.
Initiation and titration
It is clear from the above that adverse events in response to initiation of ACE inhibition, while rare, are potentially important and are unpredictable. On this background, all national28 and international27 guidelines for the management of HF recommend initiation of therapy at a low dose of the individual agent, and careful monitoring of the response of both blood pressure and renal function. This is simple, sound advice.
Hydralazine and nitrates
Hydralazine is a direct-acting vasodilator acting predominantly on the arterial side of the circulation. Nitrates are vasodilators with marked effects on the venous circulation. Used together, the combination therapy potentially offers balanced vasodilation, reducing both preload and afterload for the failing heart.
In the earliest large-scale mortality study for patients with chronic HF, 652 patients were randomized to receive combination therapy with the combination of hydralazine and isosorbide dinitrate, prazosin (an α-blocker), or placebo.37 The study, known as VHeFT 1, showed a small benefit from the hydralazine and isosorbide dinitrate combination over the other limbs of the study.
The next step was VHeFT 2, in which 804 men with chronic HF were randomized to either the hydralazine and isosorbide dinitrate combination or enalapril.38 Two-year mortality was significantly lower in patients randomized to enalapril than hydralazine/isosorbide dinitrate, although a striking finding was that combination therapy led to a greater improvement in exercise capacity than did enalapril.
Interest in the hydralazine/nitrate combination largely waned with the results of VHeFT 2. Hydralazine is a difficult drug to use, particularly as some subjects metabolize it slowly (slow acetylators) and are at risk of developing a lupus-like syndrome with its use. Both hydralazine and nitrates are metabolized rapidly and have to be given frequently to have an effect.
However, reviews of the VHeFT programme suggested that black patients may have more to gain from hydralazine/nitrate therapy than white patients.39 The AHeFT (African-American Heart Failure Trial) was thus constructed.40 Over 1000 black patients were randomized to receive isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for HF. All the patients had dilated left ventricles, and nearly 80% were taking either an ACE inhibitor or angiotensin receptor antagonist at baseline. There was a significant improvement in outcome in patients treated with isosorbide dinitrate plus hydralazine.
The practical consequences are not clear-cut. The results lend support to the common practice of using hydralazine/isosorbide dinitrate in patients with chronic HF who for some reason cannot tolerate an ACE inhibitor or ARB. However, there is no clear-cut evidence that such an approach is appropriate in white patients. Equally, it is not clear whether all people with HF who identify themselves as being black should be offered hydralazine/isosorbide dinitrate.
Other vasodilators
An important finding from VHeFT 238 was that hydralazine/isosorbide dinitrate had a greater effect on exercise capacity than enalapril although a lesser effect on mortality. The finding emphasizes the importance of the neurohormonal hypothesis for HF—ACE inhibitors are not mediating their benefit primarily through vasodilatation. Drugs with more pure vasodilating activity, such as flosequinan, do improve exercise capacity quite strikingly,41 but are associated with a worse outcome.42
Amlodipine, a dihydropyridine calcium antagonist, has been extensively tested in HF. The PRAISE trial43 suggested that amlodipine might be beneficial for patients with HF due to causes other than ischaemic heart disease. PRAISE-2 studied 1652 patients with severe HF and a normal coronary angiogram randomized to amlodipine or placebo.44 There was no difference in outcome between the two groups. It is possible that the difference between PRAISE and PRAISE-2 is explained by a beneficial effect of amlodipine in patients with HF due to occult coronary heart disease: such patients in PRAISE would have been analysed together with patients with dilated cardiomyopathy as there was no requirement for coronary angiography on PRAISE, only PRAISE-2.
The general conclusion from the PRAISE study programme is that there is no role for specific vasodilators in patients with chronic HF, but that if a patient has angina or blood pressure difficult to control with standard HF medication, then amlodipine is a safe additional therapy.
Summary
The ACE inhibitors are among the most investigated groups of drugs in cardiovascular medicine. Twenty-five years after the first inkling that ACE inhibitors may have a place in the management of HF, they remain a central component of the physician’s armamentarium. As a class, ACE inhibitors have transformed not only the management of patients with HF, but also our understanding of this complex syndrome. All efforts should be made to initiate, and maintain at appropriate doses, treatment with ACE inhibitors in all patients with LVSD. We, and our patients, are fortunate to have them.
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